U.S. Pat. No. 5,985,848, U.S. Pat. No. 6,066,722 and U.S. Pat. No. 6,228,741 describe nucleoside analogues that are inhibitors of purine nucleoside phosphorylases (PNPs) and purine phosphoribosyl-transferases (PRTs). The analogues are useful in treating parasitic infections, T-cell malignancies, autoimmune diseases and inflammatory disorders. The analogues are also useful for immunosuppression in organ transplantation.
U.S. Pat. No. 6,693,193 describes a process for preparing certain PNP inhibitor compounds. This application recognises the compounds as PNP inhibitors and addresses a need for simpler methods of preparing them. U.S. Ser. No. 10/363,424 discloses further nucleoside analogues that are inhibitors of PNPs and PRTs.
PNPs catalyse the phosphorolytic cleavage of ribo- and deoxyribonucleosides, for example those of guanine and hypoxanthine, to give the corresponding sugar-1-phosphate and guanine, hypoxanthine or other purine bases.
Humans deficient in PNP suffer a specific T-cell immunodeficiency due to an accumulation of dGTP which prevents proliferation of stimulated T lymphocytes. Inhibitors of PNP are therefore immunosuppressive, and are active against T-cell malignancies and T-cell proliferative disorders.
Nucleoside hydrolases (NHs) catalyse the hydrolysis of nucleosides. These enzymes are not found in mammals but are required for nucleoside salvage in some protozoan parasites. Some protozoan parasites use nucleoside phosphorylases either instead of or in addition to nucleoside hydrolases for this purpose. Inhibitors of nucleoside hydrolases and phosphorylases can be expected to interfere with the metabolism of the parasite and can therefore be usefully employed against protozoan parasites.
The imino sugar part of the compounds described in the patent specifications referred to above has the nitrogen atom located between C-1 and C-4 so as to form 1,4-dideoxy-1,4-imino-D-ribitol compounds. The location of the nitrogen atom in the ribitol ring may be critical for binding to PNP and NH enzymes. In addition, the location of the link between the sugar moiety and the nucleoside base analogue may be critical for enzyme inhibitory activity. The compounds described above have that link at C-1 of the sugar ring.
The applicants have also developed other nucleoside phosphorylase, phosphoribosyltransferase, and hydrolase inhibitors, where the location of the nitrogen atom in the sugar ring is varied and, additionally, where two nitrogen atoms form part of the sugar ring. Alternative modes of linking the sugar part and the base analogue have also been investigated, resulting in a class of inhibitors where the sugar moiety is linked to the nucleoside base analogue via a methylene bridge. These other inhibitors are described in U.S. Ser. No. 10/395,636.
It has been considered to date that the three dimensional structure of the imino sugar ring of the above compounds is critical for effective binding to PNPs and NHs, and therefore inhibition of these enzymes. The ring structure constrains the spatial locations that important functional groups, such as the imino nitrogen and various hydroxyl groups, can adopt when interacting with the enzymes. These steric constraints have previously been considered to be necessary for binding of the compounds in the active site of the enzymes. In the absence of such steric constraints, compounds would not be expected to be proficient binders to the enzyme active sites and consequently would not be effective inhibitors of the enzymes.
The view that the imino sugar ring is important for effective enzyme inhibition is reinforced in J. Biol. Chem., 2005, 280, 30320-30328, which describes an investigation of transition state analogue interactions with human and Plasmodium falciparum PNPs. Inhibition activities against these PNPs for various nucleoside analogues are described. The structure of the great majority of the analogues contains an imino sugar ring. Two compounds are described where that ring is, in effect, opened to give hydroxyethyl and hydroxypropyl substituents on the amino nitrogen.
J. Med. Chem., 2006, 49, 6037-6045 also describes a number of PNP inhibitor compounds, some of which comprise an imino sugar ring moiety and some of which have an acyclic N-hydroxyethyl amino group. Those compounds that do exhibit PNP inhibition activity are considered to have only moderate potency (inhibition constants at the micromolar or nanomolar level).
While there is some understanding of the structural features of compounds needed for binding to PNP enzymes and inhibition activity, it remains difficult to predict with certainty whether a compound will be a weak or potent inhibitor, or even an inhibitor at all, until the compound is synthesised and tested in the appropriate assays. The imino sugar ring-opened compounds disclosed in above mentioned J. Biol. Chem and J. Med. Chem publications are too few and structurally disparate to serve as predictors for a general class of acyclic amine inhibitors of PNP.
The applicants have now surprisingly found that certain compounds analogous to the compounds described above, having an acyclic amine group rather than an imino ring, are effective inhibitors of human and Plasmodium falciparum PNPs.
It is therefore an object of the present invention to provide acyclic amine compounds that are inhibitors of PNPs or NHs, or to at least provide a useful choice.